Inflammatory Mediators in Airway Diseases

Airway diseases such as asthma and chronic obstructive pulmonary disease arise from complex interactions between inhaled irritants and the mucosal immune system. Central to this interplay are inflammatory mediators, comprising cytokines, chemokines, eicosanoids and growth factors, which orchestrate recruitment and activation of immune cells, including eosinophils, neutrophils and lymphocytes. Epithelial cells, once thought to play a passive barrier role, are now recognised as active participants that sense environmental triggers and release cytokines and alarmins to shape downstream responses. Dysregulated signalling through pathways such as phosphoinositide 3-kinase (PI3K), nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinases underlies persistent inflammation, airway hyperresponsiveness and structural remodelling. Advances in high-throughput profiling and animal models have illuminated distinct endotypes driven by specific mediators, paving the way for stratified therapies that target key molecular nodes with reduced off-target effects. Understanding the balance between pro-inflammatory and resolving mediators remains critical for translating mechanistic insight into interventions that improve lung function and quality of life in affected populations worldwide.

Research from Nature Portfolio

Local administration of a pan-PI3K inhibitor prodrug via inhalation has been shown to attenuate both acute and resistant asthma models while sparing systemic toxicity. By selectively blocking PI3K activity in lung tissue, this approach reduces airway inflammation, improves lung compliance and protects against irreversible fibrosis in murine studies. Complementary evidence from a meta-analysis of experimental mouse models indicates that both pan-PI3K inhibitors and selective PI3K-δ inhibitors effectively lower eosinophil and neutrophil counts, as well as Th2-type cytokines such as interleukin-4, IL-5 and IL-13. The analysis further suggests that delta-selective compounds may achieve comparable anti-inflammatory efficacy with diminished risk of off-target effects, supporting PI3K-δ as a promising therapeutic node for allergic airway inflammation.

Inflammatory Mediators in Airway Diseases publication trend

The graph below shows the total number of articles in inflammatory mediators in airway diseases across all publications each year (not limited to Nature Index journals).

Technical terms

Cytokines: Small proteins released by immune and structural cells that regulate inflammation and cell communication.

Chemokines: Subset of cytokines that guide directional migration of leukocytes to sites of tissue injury or infection.

Eicosanoids: Bioactive lipid mediators derived from arachidonic acid, including prostaglandins and leukotrienes, which modulate vascular tone and cell recruitment.

Phosphoinositide 3-kinase (PI3K): A family of lipid kinases that transduce signals from growth factors and cytokine receptors to control cell survival and inflammation.

Nuclear factor-kappaB (NF-κB): A transcription factor complex that regulates expression of pro-inflammatory genes in response to stress and microbial stimuli.

References

1. PP121, a dual inhibitor of tyrosine and phosphoinositide kinases, relieves airway hyperresponsiveness, mucus hypersecretion and inflammation in a murine asthma model. Molecular Medicine (2023).
2. Isthmin-1 attenuates allergic Asthma by stimulating adiponectin expression and alveolar macrophage efferocytosis in mice. Respiratory Research (2023).
3. Inhalation of the prodrug PI3K inhibitor CL27c improves lung function in asthma and fibrosis. Nature Communications (2018).
4. Roles of PI3K pan-inhibitors and PI3K-δ inhibitors in allergic lung inflammation: a systematic review and meta-analysis. Scientific Reports (2020).